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Osteoarthritis Supplement

Role of Sex Hormones in the Development

of Osteoarthritis
Sarah Linn, MD, Bryan Murtaugh, MD, Ellen Casey, MD

Abstract: Women older than 50 years have a considerably higher prevalence of osteoar-
thritis than men of the same age group. Although several factors have been proposed, there
is some evidence that sex hormones influence the development of osteoarthritis. This article
will focus on the basic science and clinical evidence that describe the current state of
knowledge regarding the relationship between sex hormones and the development of
osteoarthritis.
PM R 2012;4:S169-S173

INTRODUCTION
The prevalence of osteoarthritis (OA) in both men and women is comparable up to the age
of 50 years; however, the prevalence in women increases considerably after this, which
suggests a role of hormonal influences in the development of the disease [1]. Furthermore,
the prevalence of arthralgia increases in women with menopausal transition and is thought
to be due to reduction of estrogen levels [2]. The phenomenon of “arthritis of menopause”
was described as early as 1926 [2], but a clear causal relationship has yet to be determined.
This article presents the basic science and clinical evidence regarding the relationship
between sex hormones and the development of OA.

BASIC SCIENCE EVIDENCE

A key feature of OA is the deterioration of articular cartilage, marked by the breakdown of
matrix proteins via metalloproteinases. These matrix metalloproteinases (MMP) degrade
several extracellular matrix molecules, including cartilage proteoglycan and type II collagen
[3]. The specific proteins, MMP-1 (collagenase 1), MMP-3 (stromelysin 1), and MMP-13
(collagenase 3) [4,5] play a primary role in OA. Their action is modulated by several factors,
including inflammatory cytokines, such as interleukin (IL) 1␤, that enhance cartilage
degradation and tissue inhibitors of metalloproteinases (TIMP) [5]. Results of studies have
shown that OA joints have an overexpression of MMPs relative to TIMPs, which promotes
the breakdown of articular cartilage [4]. Because sex hormone receptors were found on
animal and human chondrocytes, studies focused on understanding the role of sex hor-
mones in OA [6,7]. Most of the basic science research to date has focused on whether sex
hormones directly influence cartilage degradation or whether they affect modulatory S.L. Department of Physical Medicine and
proteins, such as MMPs. Rehabilitation, Rehabilitation Institute of Chi-
cago, Chicago, IL.
Disclosure: nothing to disclose

Estrogen B.M. Department of Physical Medicine and

Rehabilitation, Rehabilitation Institute of Chi-
Numerous studies have been carried out to evaluate the relationship between estrogen and cago, Chicago, IL.
Disclosure: nothing to disclose
the development of OA. As described below, estrogen has been demonstrated to have both
protective and detrimental effects on articular cartilage. E.C. Department of Physical Medicine and
Rehabilitation, Rehabilitation Institute of Chi-
Protective Effects of Estrogen. In 2005, Claassen et al [8] showed that estrogen added cago, Chicago, IL. Address correspondence
to: E.C., 345 E Superior St, Chicago, IL
to articular chondrocytes in vitro provided an antioxidative effect and protected the 60611; e-mail: ecasey@ric.org
chondrocytes from reactive oxygen changes that play a role in OA. In 2007, Ma et al [9] used Disclosure: nothing to disclose
ovariectomized female and castrated male rats to demonstrate a protective role of estrogen Disclosure Key can be found on the Table of
on cartilage degradation. Interestingly, the protective effect of estrogen appears to be Contents and at www.pmrjournal.org

PM&R © 2012 by the American Academy of Physical Medicine and Rehabilitation

1934-1482/12/$36.00 Vol. 4, S169-S173, May 2012 S169
Printed in U.S.A. DOI: 10.1016/j.pmrj.2012.01.013
S170 Linn et al
sex-specific because the chondroprotective effect was found
only in the female rats [9]. The sex-specific nature of estrogen
on articular cartilage is further supported by 2 additional
studies. Kinney et al [10] showed that, although the chon-
drocytes of both males and females are positive for estrogen-
receptor ␣ messenger RNA (mRNA), only female chondro-
cytes respond to estradiol supplementation [10].
Furthermore, Claassen et al [3] showed that estradiol had a
sex-dependent effect on MMPs and TIMPs. An additional
study, by Bay-Jensen et al [11], used urinary CTX-II (a
marker of type II collagen destruction) to evaluate the role of
estrogen on articular cartilage. Results of this study showed
elevated levels of urinary CTX-II in ovariectomized rats that
corresponded to similar elevations seen in postmenopausal
women [11]. Another study also showed that urinary CTX-II
levels were reduced in ovariectomized rats given exogenous
estrogen compared with rats that were not supplemented
[12].
Detrimental Effects of Estrogen. In 1993, Tsai and Liu
[13] conducted a study of ovariectomized rabbits that were
given intraarticular injections of estradiol benzoate. The knee
joints injected with estradiol demonstrated several patho-
logic changes consistent with OA, including fibrillation and
erosion of articular cartilage and exposure of subchondral
bone. In 2004, Richette et al [5] added estradiol and IL-1␤ to
chondrocytes in vitro. At low doses, estradiol inhibited IL-
1␤, but the inflammatory effects of IL-1␤ were enhanced at
high doses of estrogen.
Testosterone
Although chondrocytes in both males and females have tes-
tosterone receptors, testosterone appears to have a modula-
tory effect only on male chondrocytes [14]. Ma et al [9]
conducted in vivo investigations in male mice (orchiectomy
versus control) and determined that intact mice demon-
strated more severe OA. Furthermore, castrated male mice
supplemented with dihydrotestosterone developed severe
OA comparable with that in intact mice.
Dehydroepiandrosterone
Dehydroepiandrosterone (DHEA), a circulating steroid hor-
mone that is a precursor to estrogen and testosterone in
humans, is postulated to be protective from the development
of OA by inhibiting the inflammation within articular joints.
To test this theory, Wu et al [15] created a rabbit model of OA
after anterior cruciate ligament transection. They found that
intra-articular injection of DHEA into this group of rabbits
resulted in a significant reduction in the histologic score of
OA. Furthermore, there was a significant decrease in the
mRNA expression of MMP-3 in cartilage and synovium, and
an increase in the mRNA expression of TIMP-1 in the group
given intra-articular DHEA. Similarly, Jo et al [16] used a
SEX HORMONES IN THE DEVELOPMENT OF OA
rabbit model with anterior cruciate ligament transection,
which also demonstrated less severe cartilage damage in the
knees that received DHEA injections compared with the
control group. Further gene expression analysis showed that
mRNA expression of IL-1␤, MMP-1, and MMP-3 were re-
duced in the cartilage of the DHEA-treated joints.
CLINICAL EVIDENCE
Although a potential connection between menopause and the
development of OA was first described in 1926, the first
clinical report of a sudden onset of postmenopausal multi-
joint OA was published in a cohort of women in 1952 [1,2].
Since that time, a causal or modulatory role of endogenous
and exogenous sex hormones has been examined. A variety
of metrics have been used, including biomarkers, radio-
graphs, magnetic resonance imaging (MRI), or use of joint
replacement as a clinical endpoint.
Relationship of Endogenous and
Exogenous Sex Hormones and OA
Endogenous. The literature contains a limited number
of articles about investigations of the relationship between
endogenous sex hormones and OA. One of the largest
cohort studies occurred over a 10-year period and focused
on the relationship between endogenous sex hormones
and radiographic OA as well as laboratory parameters
[17]. Subjects with low estradiol levels were found to have
an increased risk of incident OA based on radiographs,
and those with low 2-hydroxyestrone (a breakdown prod-
uct of estradiol catabolism with weak estrogenic activity)
were at greater risk for both incident and prevalent knee
OA. The researchers postulated that higher 2-hydroxye-
strone levels could delay the development of knee OA
through inhibition of leukotriene synthesis in the arachi-
donic acid pathway. Furthermore, because leukotrienes
play a role in pain and inflammation, a lack of estrogen and
its metabolites may enhance the painful symptoms associ-
ated with OA in addition to playing a role in structural
changes associated with joint degeneration [18]. Another
cross-sectional study showed a significant association be-
tween estrogen deprivation due to menopause and in-
creased urinary CTX II in asymptomatic women, which
suggests increased cartilage breakdown in postmeno-
pausal women compared with premenopausal women
[11]. These findings are limited by a small sample size and
the fact that there was no measurement of serum estrogen
levels.
There have been other studies that showed no correlation
between endogenous sex hormones and OA. In a study of
white women with a mean age of 74 years, similar concen-
trations of serum estrone, estradiol, testosterone, and andro-
stenedione were found in subjects with mild, moderate, or
PM&R
severe hand OA based on radiographic findings, which sug-
gests that the concentrations of endogenous sex hormones do
not affect OA severity [19]. This lack of association also was
supported in a study that failed to demonstrate any correla-
tion between estrogen-related hormonal events (age at men-
arche or menopause, rates of hysterectomy, or oral contra-
ceptive use) and the presence of OA [20]. One systematic
review of 16 studies that examined the association between
OA and aspects concerning both the fertile period and the
menopause period, concluded that most evidence pointed
toward no relation or at least conflicting results between
female hormonal aspects and OA [21].
MRI has also been used to evaluate the association be-
tween endogenous sex hormones and OA in asymptomatic
adults, including 2 cross-sectional studies and one small,
2-year cohort study. The cross-sectional studies demon-
strated a positive association between testosterone and me-
dial tibial plateau cartilage volume in men as well as a positive
association between sex hormone binding globulin and pa-
tella bone volume in women [22,23]. Although increased
testosterone was associated with greater cartilage volume in
the cross-sectional study in men, it was associated with
increased cartilage loss after 2 years in a cohort study [24].
In summary, there is some evidence that suggests an
association between endogenous estrogens with lower carti-
lage turnover and some inconsistent evidence for the associ-
ation of reduced endogenous estrogen and its metabolites
with radiographic OA. Furthermore, the association between
serum testosterone and cartilage volume is unclear.
Exogenous. The relationship between exogenous sex hor-
mones, such as hormone replacement therapy (HRT), and
OA has also been examined. One randomized controlled trial
found that there were decreased urinary CTX-I and CTX-II
levels after 1 year of treatment with either oral or transdermal
estradiol therapy, which indicated decreased cartilage break-
down [25]. Results of another randomized controlled trial
found decreased serum CTX-I and urinary CTX-II levels with
levormeloxifene use over 1 year [26].
When considering the effect of HRT on radiographic
findings of OA, the Ulm Osteoarthritis Study reported no
significant association between HRT use and radiographic
hip, knee, or hand OA in 475 women [27]. Another
cross-sectional study reported no significant association
between current or lifetime HRT use and prevalence of
distal interphalangeal or carpometacarpal OA, although
there was an association with HRT use and increased
severity of Heberden nodes [28]. However, women from
the Study of Osteoporotic Fractures who were currently
using oral estrogen had a significantly reduced risk of any
OA of the hip and moderate-to-severe radiographic man-
ifestation of OA [29]. Current users who had taken estro-
gen for at least 10 years had a greater reduction in the risk
of any OA of the hip compared with that of users for less
than 10 years. Current estrogen use for 10 years or longer
Vol. 4, Iss. 5S, 2012 S171
was also associated with a nonsignificant trend for a re-
duced risk of moderate-to-severe symptomatic disease.
There was a nonsignificant lower risk of OA of the hip
among long-term users who stopped taking estrogen less
than 10 years before their assessment, and no reduction
was observed in risk among the subjects who stopped
taking estrogen more than 10 years prior to the study [29].
These results support that women who take and remain on
HRT for several years may be protected against the devel-
opment or progression of radiographic findings of OA of
the hip. The Chingford Study, a cross-sectional study of
women in the general population, showed that, for current
users of HRT (⬎12 months), there was a significant pro-
tective effect for knee OA defined by the Kellegren and
Lawrence grade for osteophytes and a similar but not
significant effect for moderate joint space narrowing of the
knee and for distal interphalangeal OA. For former users
of HRT (⬎12 months), there was no overall protective
effect [30]. Yet, on radiographs taken after 4 years of
follow-up, current HRT was only associated with a non-
significant protective effect for incident knee osteophytes
[31]. These results were in accordance with those of the
Framingham Osteoarthritis Study, which showed a mod-
est but nonsignificant protective effect for both radio-
graphic OA and severe radiographic OA in women who
reported estrogen use at 2 or more examinations [32,33].
After 8 years of follow-up, current estrogen users had a
50% nonsignificant reduction in the risk of incident radio-
graphic knee OA compared with never users and a trend
toward decreased risk of progression of knee OA com-
pared with women who never used HRT [34]. With regard
to findings of OA on MRI, one cross-sectional study found
that there was greater tibial cartilage among estrogen users
[35], whereas one cohort study and one cross-sectional
study found no association between estrogen replacement
therapy and patella cartilage volume [36] and tibial carti-
lage loss [37].
The effect of HRT on the risk of OA leading to joint
replacement has also been evaluated. One case-reference
study showed an increase in the risk of developing severe
knee OA, which led to prosthetic surgery in women re-
ceiving HRT in the Swedish Knee Arthroplasty Register,
but this study did not specify HRT duration or the indica-
tion for the HRT prescription [38]. In contrast, one ran-
domized controlled trial showed that women who re-
ceived unopposed estrogen had lower rates of joint
replacement, although this was not found in those women
who received both estrogen and progesterone [39].
In summary, the majority of the evidence suggests a
protective effect of exogenous estrogen on cartilage and
bone turnover. However, it remains uncertain whether it
also affects radiographic OA, cartilage volume on MRI, or
joint replacement due to a lack of long-term studies.
Although results of some studies have concluded that HRT
S172 Linn et al
may have a beneficial effect on the structural progression
of OA, particularly in the knee and hip, the symptomatic
action of HRT on OA appears to be negligible [40]. The
observation that only long-term HRT appears to be bene-
ficial should be carefully deliberated while assessing HRT
for management of OA. When considering the risk-versus-
benefit ratio, the health risks of HRT may outweigh the
potential benefits, and HRT cannot be recommended as a
first-line treatment against progression of OA, given the
current level of evidence [40].
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